Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design

Abstract

BackgroundConventional randomized placebo-controlled study design assumes the absence of drug*placebo interaction. We hypothesized the presence of such an interaction and that conventionally estimated drug effect might be biased. The objectives of the study were to determine the drug*placebo interaction effect (main) and compare conventionally estimated and interaction model-estimated drug effects (secondary).MethodsWe used a hybrid of balanced placebo and randomized placebo-controlled designs. Four hundred eighty healthy volunteers were randomized to three groups. The first received hydroxyzine (25 mg) described as hydroxyzine or placebo, the second received placebo described as hydroxyzine or placebo, and the third received hydroxyzine and placebo described as unknown; each in a randomized crossover design. Seven participants failed to crossover. Group assignment was concealed from participants and study coordinators. Coordinators were blinded to group and intervention assignment. Participants and coordinators were deceived as to study objectives. Main outcomes were mean area-under-the-curve of drowsiness (therapeutic outcome) and mouth-dryness (adverse outcome), self-reported on 100 mm visual analog scale over 7 h. Drug, placebo, placebo + interaction, and total effects were estimated using analysis of covariance by comparing received hydroxyzine/told placebo to received placebo/told placebo, received placebo/told hydroxyzine to received placebo/told placebo, received hydroxyzine/told hydroxyzine to received hydroxyzine/told placebo, and received hydroxyzine/told hydroxyzine to received placebo/told placebo, respectively. Drug effect was also conventionally estimated in the third group.ResultsMean (SD) age was 31.4 (6.6) years, 65% were males. There was significant difference between placebo + interaction effect and placebo effect for both drowsiness and mouth-dryness with a mean difference (95% confidence interval) of 35.1 (5.6 to 64.6) and 23.8 (2.4 to 45.2) mm*hr, respectively. Total effect was larger than the sum of drug and placebo effects for drowsiness (139.7 (109.8 to 169.6) vs. 99.1 (68.2 to 130.0) mm*hr) and mouth-dryness (63.6 (41.1 to 86.1) vs. 34.7 (11.1 to 58.4) mm*hr). Conventionally estimated drug effect was larger than interaction model-estimated drug effect for drowsiness (69.2 (45.5 to 92.8) vs. (58.3 (31.6 to 85.0) mm*hr) and mouth-dryness (19.9 (5.3 to 34.5) vs. 9.5 (−9.2 to 28.1) mm*hr).ConclusionsThere is significant and important drug*placebo interaction effect that may bias conventionally estimated drug effect.Trial registrationClinicalTrial.gov identifier: NCT01501591 (registered December 25, 2011).

The Placebo Effect in Pain Therapies

“…These effects depend on an interaction between modulatory central nervous systems and peripheral pain mechanisms. A few studies suggest that the placebo effect may increase the half-life of substances such as caffeine (148) and interact with medications (149), therefore biasing the results of clinical trials and challenging the concept that placebo and drug effects are additive. Yet it remains to be fully elucidated how being aware of receiving a pain treatment might alter the drug’s pharmacokinetics.…”

Placebo and Active Treatment Additivity in Placebo Analgesia: Research to Date and Future Directions

“…Indeed, we could identify only 12 studies, which examined heterogeneous samples spanning from the treatment of attention deficit hyperactivity disorder with methylphenidate (Pelham, Hoza, Kipp, Gnagy, & Trane, 1997; Pelham et al, 2002) to the sedative effects of the antihistamine hydroxyzine (Hammami et al, 2016). Given that within a single modality the placebo effect may have different additive relationships with different treatments, the application of findings from one modality to another poses substantial problems.…”

How do they add up? The interaction between the placebo and treatment effect: A systematic review

“…The 30 included studies were published between 1959 and 2017. Of these, 19 (63%) involved healthy volunteers, 10,20,[26][27][28][29][30][31][32][33][34][35][37][38][39][40]44,48,49 with six of these using painful stimulus. 10,[31][32][33]37,40 Eleven other studies tested symptomatic patients 7,9,16,25,36,41,43,[45][46][47] : six for pain management, 9,16,25,36,41,45 two for psychological disorders, 7,46 two for asthma symptoms, 42,43 and one for sexual disorders.…”

“…The presence or not of interaction was evaluated in most included studies by comparing the variables in each group in BPD with analysis of variance (ANOVA) or covariance (ANCOVA) 7,10,18,20,25–34,36,38,42–46,48 . When it was detailed, the level of significance chosen was 0.05 10,20,25–28,30,32,33,38,39 (except for Bergmann et al at 0.10) 9 . Linear regression models were also used to demonstrate interaction 10,23,35,38–41 …”